epi-001 and Prostatic-Neoplasms

epi-001 has been researched along with Prostatic-Neoplasms* in 6 studies

Reviews

1 review(s) available for epi-001 and Prostatic-Neoplasms

ArticleYear
A critical update on the strategies towards modulators targeting androgen receptors.
    Bioorganic & medicinal chemistry, 2020, 07-01, Volume: 28, Issue:13

    Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. In this review, we discussed some new strategies for targeting androgen receptors through degradation pathways as potential treatments for prostate cancer.

    Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Heat-Shock Proteins; Humans; Male; Prostatic Neoplasms; Proteolysis; Receptors, Androgen; Signal Transduction; Thiohydantoins; Ubiquitination

2020

Other Studies

5 other study(ies) available for epi-001 and Prostatic-Neoplasms

ArticleYear
Differential proteome expression analysis of androgen-dependent and -independent pathways in LNCaP prostate cancer cells.
    Experimental cell research, 2017, 10-01, Volume: 359, Issue:1

    Prostate cancer (PC) is one of the leading causes of cancer death in men. It commonly develops in older males, but the number of younger men diagnosed with the disease has increased in recent years. Hormone therapies, such as chemical and surgical methods that inhibit androgen synthesis or androgen receptor (AR) activation, have been used for advanced disease. However, castration-resistant PC (CRPC), which exhibits androgen-independent mechanisms for activating AR, develops after a few years of such treatment and no therapy is available. In this study, we examined differences in the proteomes associated with the androgen-dependent (DHT treatment) and -independent (FSK, forskolin treatment) AR signaling conditions in LNCaP prostate cancer cells. Moreover, we used EPI-001, which inhibits AR-mediated transcriptional activity, to examine whether the observed differences in protein expression were directly affected by AR-mediated mechanisms. A total of 213 protein spots were matched in our 2-dimensional gel electrophoresis (2DE) analysis and 8 proteins with significant expression changes in our 5 different treatment groups were identified by mass spectrometry. Among these proteins, expression levels of PEPCK-M, catalase, tubulin alpha chain, alpha-enolase, and endoplasmic reticulum resident protein 29 were significantly altered by DHT and the levels of HSP 90 and EF-Tu were changed by FSK. These changes were blocked by EPI-001 in DHT-regulated proteins, PEPCK-M, catalase, and tubulin alpha chain and FSK-regulated EF-Tu protein. The results from our immunohistochemical analysis using in vivo xenograft models were consistent with the 2DE data. We therefore report the first identification of differences in proteins that are significantly regulated under androgen-dependent and -independent AR signaling conditions. Our findings could suggest a possible molecular mechanism through which AR is activated in the absence and/or presence of androgen, and might help explain the inhibitory action of EPI-001 on CRPC.

    Topics: Androgens; Animals; Benzhydryl Compounds; Cell Line, Tumor; Chlorohydrins; Colforsin; Dihydrotestosterone; Electrophoresis, Gel, Two-Dimensional; Humans; Immunohistochemistry; Male; Mice; Peptide Elongation Factor Tu; Phosphoenolpyruvate Carboxykinase (ATP); Prostatic Neoplasms; Proteome; Proteomics; Signal Transduction; Tandem Mass Spectrometry; Tubulin; Xenograft Model Antitumor Assays

2017
EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.
    ACS chemical biology, 2016, 09-16, Volume: 11, Issue:9

    Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.

    Topics: Benzhydryl Compounds; Chlorohydrins; Humans; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Transcriptional Activation

2016
EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer.
    Oncotarget, 2015, Feb-28, Volume: 6, Issue:6

    The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARĪ³). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR NTD, and reduced AR expression. EPI-001 inhibited growth of AR-positive and AR-negative PCa cell lines, with the highest sensitivity observed in LNCaP cells. Overall, this study provides new mechanistic insights to the chemical biology of EPI-001, and raises key issues regarding the use of covalent inhibitors of the intrinsically unstructured AR NTD.

    Topics: Androgen Receptor Antagonists; Benzhydryl Compounds; Cell Line, Tumor; Cell Proliferation; Chlorohydrins; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Transfection

2015
An androgen receptor N-terminal domain antagonist for treating prostate cancer.
    The Journal of clinical investigation, 2013, Volume: 123, Issue:7

    Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.

    Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents, Hormonal; Benzhydryl Compounds; Cell Proliferation; Chlorocebus aethiops; Chlorohydrins; Click Chemistry; COS Cells; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Luciferases; Male; Mice; Mice, Inbred NOD; Mice, SCID; Orchiectomy; Prostatic Neoplasms; Protein Binding; Protein Structure, Tertiary; Receptors, Androgen; Stereoisomerism; Transcriptional Activation; Tumor Burden; Xenograft Model Antitumor Assays

2013
Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.
    Cancer cell, 2010, Jun-15, Volume: 17, Issue:6

    Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.

    Topics: Androgen Receptor Antagonists; Androgens; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Benzhydryl Compounds; Castration; Cell Line, Tumor; Cell Proliferation; Chlorohydrins; CREB-Binding Protein; DNA; Gene Expression; Humans; Ligands; Male; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Structure; Neoplasm Recurrence, Local; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Receptors, Androgen; Receptors, Steroid; Response Elements; Serine Endopeptidases; Transcriptional Activation; Xenograft Model Antitumor Assays

2010